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CASE REPORTS

Severe folate deficiency anemia associated with the use of a PARP inhibitor (olaparib) in a patient with fallopian tube cancer

Binoy Yohannan1, Kristi McIntyre2, Mark Feldman∗1

1Department of Internal Medicine, Texas Health Presbyterian Hospital, Dallas, Texas, United States 2Department of Internal Medicine, Division of Hematology and Oncology, Texas Health Presbyterian Hospital, Dallas, Texas, United States

Received: August 27, 2018 Accepted: September 24, 2018 Online Published: September 27, 2018 DOI: 10.5430/crim.v6n1p1 URL: https://doi.org/10.5430/crim.v6n1p1

ABSTRACT

Treatment of cancer patients with olaparib (PARP inhibitor) is associated with an increased risk of anemia, which is seen in a majority of treated patients. However, symptomatic anemia requiring transfusion is rare. Olaparib-induced anemia can be secondary to bone marrow suppression, hemolysis or folate deficiency. We report a case of new onset severe folic acid deficiency anemia in a patient with breast and relapsed fallopian tube cancer being treated with olaparib. Complete blood count on admission showed a hemoglobin of 4.2 g/dl and serum folate was undetectable (< 1.6 ng/ml; reference range 7-31.4 ng/ml). This is the second report of olaparib-induced folate deficiency anemia. She received three units packed red cell transfusion and parenteral folic acid supplementation and improved symptomatically. This case highlights the importance of recognizing folate deficiency as a reversible cause of anemia with PARP inhibitor therapy. Key Words: Fallopian tube cancer, Olaparib, Folate deficiency anemia

1.I NTRODUCTION folate deficiency.[1] Poly ADP ribosyl polymerase (PARP) is an enzyme that repairs DNA damage in tumor cells and Folic acid (vitamin B9) is a water-soluble vitamin which has several vital functions. It is required for the repair and in normal cells. With the goal of selectively impairing DNA methylation of DNA and acts as a cofactor in numerous bi- repair in tumor cells, PARP inhibitors such as olaparib are be- ological reactions. It regulates cell division and plays an ing used to treat recurrent ovarian, fallopian tube and breast important role in erythropoiesis. Folic acid deficiency is cancers. The PARP-1 enzyme is involved in the repair of usually seen in physiological conditions such pregnancy and single-stranded DNA breaks, while PARP-2 plays a pivotal lactation due to increased metabolic demand for this vita- role in hematopoietic homeostasis by determining the sur- [2] min. Other causes include chronic alcoholism, intestinal vival of stem cells and their response to oxidative stress. malabsorption, hemolytic anemia and exfoliative skin dis- High levels of reactive oxygen species are observed in PARP- eases. Certain drugs such as phenytoin and dihydrofolate 2 deficient hematopoietic stem cells, resulting in DNA dam- reductase inhibitors such as methotrexate also may cause age and because the DNA repair mechanism is ineffective, ∗Correspondence: Mark Feldman, MD; Email: [email protected]; Address: Department of Internal Medicine, Texas Health Presbyte- rian Hospital, Dallas, Texas, 75231, United States.

Published by Sciedu Press 1 http://crim.sciedupress.com Case Reports in Internal Medicine 2019, Vol. 6, No. 1 it leads to activation of p53-dependent apoptotic pathways. continued for 6 years but was eventually discontinued due to This accelerated cellular apoptosis may be compensated for progression of disease and bevacizumab-induced nephrotic by an increase in turnover of the progenitor cells, but this syndrome. She was switched to docetaxel for the next 2 replicative stress limits progenitor cell differentiation and years. Two years prior to the current admission, she was di- makes the cells more susceptible to extravascular hemolysis. agnosed with stage II B, HER2 positive breast cancer which It has been shown that deficiency of the enzyme PARP-2 in was treated with mastectomy followed by transtuzumab fol- mice results in a decrease in RBC count, enlarged erythrocyte lowed by maintenance therapy with anastrozole. Docetaxel size, the appearance of Howell-Jolly bodies and a reduced was discontinued. Genetic testing for a BRCA mutation was lifespan of circulating erythrocytes.[3] negative. The fallopian tube cancer was progressing despite multiple types of prior chemotherapy and she was started on Here we report a case of severe folate deficiency anemia olaparib 300 mg twice daily 2 months prior to the current induced by the PARP inhibitor olaparib in a patient with admission. Other medical problems included hypertension, advanced fallopian tube cancer. bipolar disorder and gastroesophageal reflux disease. A fam- ily history included a maternal grandmother with gastric 2.C ASE PRESENTATION cancer at age 76, a maternal first cousin with breast cancer A 76-year-old female with advanced fallopian tube cancer at age 45, and a maternal aunt with ovarian cancer (BRCA with peritoneal carcinomatosis on olaparib therapy presented negative). to the emergency department with fatigue, generalized weak- ness and dyspnea on exertion. She denied fever, chills, night On physical examination her temperature was 98.3◦F with sweats, weight loss, easy bruising or bleeding. She also de- blood pressure 100/68 mmHg, pulse 99 beats per min and nied abdominal pain, melena and hematochezia. There was respiratory rate 18 per minute. She looked very pale but had no history of alcohol abuse or any dietary restriction. no icterus or lymphadenopathy. She had moist mucous mem- branes and the oropharynx was clear with no evidence of She had stage III B high grade papillary serous carcinoma cheilitis or glossitis. She had a soft ejection systolic murmur of the fallopian tube with omental metastasis that was diag- at the apex and normal vesicular breath sounds. Her abdomen nosed 11 years ago. At that time, peritoneal washings were was soft and non-tender without hepatosplenomegaly or as- negative for malignant cells. She underwent total abdominal cites. Neurological examination was unremarkable without hysterectomy and salpingoophorectomy followed by six cy- evidence of peripheral neuropathy. Digital rectal examina- cles of systemic chemotherapy with taxol and carboplatin and tion showed no hemorrhoids or fissures and a fecal occult consolidation with three cycles of intraperitoneal chemother- blood test was negative. apy with the same drugs. One year later, she had a biopsy- proven intraabdominal recurrence that was treated with car- Her routine blood tests on admission showed profound ane- boplatin, gemcitabine and bevacizumab. This therapy was mia with a hemoglobin level of 4.1 g/dl (see Table 1).

Table 1. Laboratory test results before and after olaparib treatment 6 months prior 2 months prior Reference range Admission 2 week follow up# to admission to admission* Hemoglobin (g/dl) 12-15 10.3 12.1 4.1 9.1 Hematocrit (%) 34.9-44.5 33 37 12.2 27 MCV (fl) 80-96 107 98.3 96 95 Reticulocyte count (%) 0.5%-1.5% 0.39% 7.42% WBC count/mm3 4,500-11,000 9,500 4,600 10,000 6,700 Platelet count/mm3 150,000-400,000 210,000 177,000 200,000 236,000 Serum ferritin (ng/ml) 20-200 215 Serum iron (µg/dl) 40-155 233 Serum transferrin (mg/dl) 173-360 182

Serum vitamin B12 (ng/L) > 300 ng/L 713 995 Serum folic acid (ng/ml) 7-31.4 ng/ml 10.0 undetectable 54.0 Note. * Prior to beginning olaparib treatment; # After discontinuing olaparib and starting 3 mg folic acid daily

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The platelet and white blood cell counts were normal. Serum patient did not appear to be actively hemolyzing since her folate was undetectable (< 1.6 ng/ml; reference range, 7- reticulocyte count was low and the indirect serum bilirubin 31.4 ng/ml) confirming severe folic acid deficiency. Serum level was normal. Folate deficiency could also be due to B12, iron studies and a coagulation profile were essentially intestinal malabsorption. Dietary folate is predominantly normal. Her last recorded hemoglobin level 2 months prior present in polyglutamyl forms which undergo hydrolysis to to starting olaparib was 12.1 g/dl. monoglutamyl derivates that are absorbed both in the small intestine and colon, with a decreasing absorptive gradient She received 3 units of packed red cell transfusions and from jejunum to colon. Folate is then transported into in- 3 mg folic acid by mouth daily. The hemoglobin increased testinal epithelial cells via folate transporters which include to 9.1 g/dl and she improved symptomatically. Olaparib was the reduced folate carrier (RFC), the proton-coupled folate discontinued and she was discharged home on 3 mg folic transporter (PCFT), and the folate receptor proteins, FRα acid daily with plans to resume the olaparib at reduced dose and FRβ.[7] Nuclear respiratory factor 1 (NRF1) is a major in 6 weeks. inducible transcriptional regulator of PCFT gene expression and is under the influence of PARP-1. It can be postulated 3.D ISCUSSION that PARP-1 inhibition leads to inactivation of NRF1 and The hematological toxicity profile of PARP inhibitors is sim- thereby downregulation of PCFT expression, thus compro- ilar to many cytotoxic chemotherapy agents and includes mising intestinal folate absorption.[8] anemia, neutropenia and thrombocytopenia. The majority of anemia events in patients on olaparib therapy are mild The proximal renal tubules play a crucial role in regulating or moderate; grade ≥ 3 events are rare. Anemia in patients body folate homeostasis by reabsorbing the filtered vitamin, treated with olaparib can be multifactorial, either from bone thus preventing its losses in the urine. Theoretically, olaparib marrow failure, hemolysis or folate deficiency. Olaparib is a could reduce renal tubular folate reabsorption. PARP-1, 2 and 3 inhibitor approved in the US for the treat- The complete blood cell count should be monitored weekly ment of recurrent epithelial ovarian, fallopian tube, primary during the first month of olaparib therapy and then monthly peritoneal and germ line BRCA mutated breast cancer.[4] thereafter. Also, before starting a PARP inhibitor, clinicians Interestingly, studies of the long-term safety of olaparib have should ensure patients have recovered from the myelosup- shown that almost all patients with anemia also had evidence pression of previous cytotoxic chemotherapy.[9] If a pa- of macrocytosis, even with normal serum folate, vitamin B12 tient develops severe hematological toxicity associated with and TSH levels. The mechanism of this olaparib-induced olaparib therapy with refractory cytopenia, bone marrow macrocytic anemia is unclear.[5] biopsy and cytogenetic analysis is recommended to rule out therapy- related myelodysplastic syndrome or acute myeloid Folate deficiency can also occur in patients treated with ola- leukemia.[9, 10] parib. Of 6 ovarian cancer patients on olaparib therapy, 4 developed severe folate deficiency within 4 weeks of start- ing the drug. Three patients required an olaparib dosage 4.C ONCLUSION reduction due to transfusion dependent anemia, with a mean time to transfusion of 39 days from initiation of therapy. Severe hematologic toxicity is one of the main treatment Almost all patients had an excellent response to oral folate re- related adverse effects of PARP inhibitors in cancer pa- placement with appropriate improvement in hemoglobin and tients and therefore regular monitoring of complete blood transfusion independence.[6] It is as yet unclear what folate cell counts is recommended. Folate deficiency can occur in replacement therapy will do in terms of the anti-tumor drug cancer patients treated with olaparib and the average time efficacy of olaparib. Whereas folate deficiency is ordinarily to depletion of folate stores is 4 to 6 weeks after initiating associated with macrocytic anemia, it was not uncommon to of treatment. The exact mechanism of folate deficiency is have a normocytic anemia in these 4 ovarian cancer patients, unknown, and further studies are required to explore the as in our patient with fallopian tube cancer. Hence, the ini- potential association between PARP inhibition and the fo- tial evaluation of normocytic anemia in a cancer patient on late pathway. Also, it is critical for clinicians to be aware olaparib therapy should include serum folate levels. of folate deficiency as a reversible cause of anemia, as the folate supplements can improve the safety and tolerability of The mechanism of severe folate deficiency in cancer pa- olaparib therapy. tients treated with PARP inhibitors such as olaparib is not clearly understood. It could be secondary to high folate con- CONFLICTS OF INTEREST DISCLOSURE sumption from hemolysis and increased RBC turnover. Our The authors declare that they have no competing interests.

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